Gastroresistant pharmaceutical formulations containing rifaximin

ABSTRACT

The object of the invention consists of pharmaceutical formulations containing rifaximin in the shape of microgranules made gastroresistant by an insoluble polymer at pH values between 1.5 and 4.0 and soluble at pH values between 5.0 and 7.5, by their preparation and by their use in the manufacture of medicinal preparations useful in the treatment of inflammatory bowel diseases (IBD) and mainly Crohn&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATION

This application is a 35 USC §371 National Phase Entry Application fromPCT/EP2006/002022, filed Mar. 6, 2006.

The object of the invention consists of pharmaceutical formulationscontaining rifaximin in the shape of microgranules made gastroresistantby an insoluble polymer at pH values between 1.5 and 4.0 and soluble atpH values between 5.0 and 7.5, by their preparation and by their use inthe manufacture of medicinal preparations useful in the treatment ofinflammatory bowel diseases (IBD) and mainly Crohn's disease.

BACKGROUND OF THE INVENTION

The intestinal apparatus is affected by many inflammatory diseasesgenerally capped as inflammatory bowel diseases. In particular, Crohn'sdisease is a severe chronic inflammatory disease affecting variouslevels of the digestive tract, from the mouth to the anus, particularlyit can be observed in the last portion of the small intestine, eitherthe ileum, the colon or both and sometimes in the mucous membrane of thecolon and in the anal region as well. In the interested intestinal part,inflammation, swelling and ulceration occur in the whole intestinal wallcausing stenosis, bleeding ulcers and pain, while the non-affectedtissue portions appear normal. Crohn's disease exhibits alternateperiods of inflammatory symptoms of variable gravity with symptoms suchas: diarrhoea, abdominal pain, weight loss often accompanied by rhagadesor peri-rectal fistulas. From two-thirds to three-quarters of patientswith Crohn's disease require surgery at some point in their lives.Surgery is used either to relieve symptoms that do not respond tomedical therapy or to correct complications such as blockage,perforation, abscess, or bleeding in the intestine.

The role of the intestinal bacterial flora in the etiopathogenesis ofthe intestinal inflammatory diseases and in particular in Crohn'sdisease is evidenced by, for example, the frequency of localization toareas with high bacteria concentrations, see Jannowitz, H. D., inInflamm. Bowel Dis., 1998, 44, 29-39; the deviation of the faecal flowdetermines remission of the endoscopic damages which reappear again atrestoration of the canalisation, see Rutgeerts, P., in Lancet, 1991,338, 771-774; experimental models, e.g., knock-out mouse for the IL-10gene or others, show that spontaneous colitis does not develop if a“germ-free” condition is maintained, see Blumberg R. S., in Curr. Opin.Immunol., 1999, 11(6), 648-56; inflammation of intestinal mucousmembrane develops after the contact with faecal material, see Harper P.H., in Gut 1985, 26(3), 279-84; after surgical “curative” therapyconsisting of ileocolic anastomosis, antibiotic treatment delays thedevelopment of both endoscopic and clinic relapses, see Cameron J. L. inAnn. Surg., 1992, 215, 546-52; and the presence of fistulae orabscess-sacs points out further the bacterial contribution to thedisease development.

Crohn's disease has previously been treated with drugs that are able todecrease or control the inflammation, e.g., cortisones, salazopirine,mesalazine, immunosupressants, specific chemotherapeutics, antibioticsand protein inhibitors of the actions of the Tumor Necrosis Factor(TNF). During the treatment of the acute phase of the inflammatory boweldisease, stronger treatments are often necessary to ensure parenteralalimentation, to reconstitute the loss of proteins, liquids and salts,to permit the intestine to rest to facilitate the cicatrisation ofulcers. The purpose of the therapy is to decrease the frequency of thereappearance of symptoms and to reduce the seriousness acute episodeswhen they appear. However, with current therapies, acute episodesrespond in about 50-70% of the cases, but relapses occur in 80% of thepatients.

Antibiotics are usually used to decrease the growth of the luminalbacteria; to decrease the inflammatory state sustained as a result ofthe bacterial growth; to reduce symptoms of the acute phase of thedisease, e.g., diarrhoea, intestinal pain and meteorism; and to preventand to cure septic complications, e.g., abscesses, fistulas and toxicstate.

The most frequently used antibiotics are systemically absorbed, forexample, metronidazole (active against some parasites along with manyanaerobic bacteria) and ciprofloxacin (active against such bacteria asE. Coli and aerobic enterobacteriace). Metronidrazol has been used at adose of 10-20 mg/kg/day for 4 months (Sunterland, L. Gut, 199132,1071-5), while ciprofloxacin has been used at a dose of 1000 mg/day for6 weeks (Colombel J. F. in Am. J. Gastoenterol., 1999, 94, 674-8), whilePrantera in Am. J. Gastoenterol., 1996, 91, 328-32, adopted thecombination of the two antibiotics using metronidazole at the dose of1000 mg/day and ciprofloxacin at the dose of 1000 mg/day for 12 weeks.The high systemic bioavailability of these antibiotics is at the root oftheir high incidence of side effects registered in long-term therapies,which negatively impacts their use. The incidence of side effects in theuse of metronidazole ranges from 10% to 20%, depending on the dose andthe treatment duration. The most frequent side-effects include metallictaste, gastric intolerance, nausea, glossitis, cephalea, vertigo,ataxia, convulsion and neurotoxicity. Peripheral neuropathy has beenrecorded in 50-85% of the long-term treated patients, which mayregresses only after several months of therapeutic interruption. Thepercentage of side effects described in ciprofloxacin studies isvariable and depends in part on the dosage and the duration of thetreatment. The most frequent of the side effects are of gastrointestinalorigin, but an increase of the transaminase and skin reactions have alsobeen frequently described. Thus, there is a need in the art for along-term treatment option for inflammatory diseases of the digestivetract, e.g., gastro enteric pathologies.

It is advantageous for pharmaceutical preparation used for treatinginflammatory bowel diseases (e.g., gastro enteric pathologies) that arebased on antibiotics to have one of more of the followingcharacteristics: intestinal level activity, low absorption, bacterialevel control in the intestinal lumen, wide spectrum of actions againstthe microbes (e.g., intestinal Gram-positive, Gram-negative, aerobic andanaerobic components), possibility of long term therapy without sideeffects, ease of administration to facilitate compliance even with thepotential of high dosage necessity, e.g., long-term dosing and/ormultiple dosing per day.

An antibiotic possessing several of these characteristics is rifaximin(INN; see The Merck Index, XIII Ed., 8304), which is characterized by awide spectrum of action against many Gram-positive and Gram-negativebacteria, including aerobic and anaerobic bacteria. Bioavailabilitystudies in healthy volunteers have shown that, when given orally, lessthan 1% of rifaximin is absorbed and it concentrates in the intestinallumen and in the faecesas described herein (Descombe J J. et al.Pharmacokinetic study of rifaximin after oral administration in healthyvolunteers. Int J Clin Pharmacol Res, 14 (2), 5′-56, (1994)). Theabsence of rifaximin absorption has been confirmed in patients affectedby chronic bowel disease, (see Rizzello, Eur. J. Clin. Pharmacol. (1998)54, 91-93). Moreover, the low absorption profile of rifaximin reducesthe incidence of side effects and the unwanted risk of pharmacologicalinteractions. Thus, rifaximin may be considered useful in the therapy ofinflammatory chronic bowel disease and particularly in Crohn's disease.The potential efficacy of rifaximin in chronic inflammatory boweldiseases has been confirmed, see Gionchetti, P., Dig. Dis. Sci., 1999,44, 1220-1, who hypothesized the use of rifaximin in patients withmoderate or severe ulcerative colitis refractory to steroid-treatment.

Rifaximin has been described in Italian Patent IT 1154655 (1980) and EP0161534 (1985), both of which are incorporated herein by reference intheir entirety for all purposes. EP 016153 discloses a process forrifaximin production using rifamycin O as the starting material (TheMerck Index, XIII Ed., 8301).

Guidance for rifaximin crystallisation and drying are described inItalian Patent Application No. MI2003A002144 (2003), in European PatentApplication No. EP 1557421 (2003); in U.S. patent application Ser. No.10/728,090 (2003) in PCT Patent Application No WO2005/044823; all ofwhich are incorporated herein by reference in their entirety for allpurposes. The experimental conditions described in these patents allowyielding polymorphic forms of rifaximin named Form α, Form β, Form γ,Form δ and Form ε, respectively.

Rifaximin is approved in certain countries for the treatment ofpathologies whose etiology is in part or totally due to intestinal acuteand chronic infections sustained by Gram-positive and Gram-negativebacteria, with diarrhea syndromes, altered intestinal microbial flora,summer diarrhoea-like episodes, traveler's diarrhoea and enterocolitis;pre- and post-surgery prophylaxis of the infective complications ingastro intestinal surgery; and hyperammonaemia therapy as coadjutant.Rifaximin is currently marketed as tablets or capsules at the dosage of100 mg and 200 mg, in a ready to use preparation for children, or asointment for the treatment of topical infections.

Studies on commercially available samples, particularly 200 mg tablets,have shown a potential usefulness of rifaximin in the prevention of therelapse of Crohn's disease after endoscopic resection. However, theabsence of a placebo group in the clinical trial does not allow to drawconfident conclusions, see Rizzello, Gut., 2000, 47, Supp. 3, A12.However, the suggested posology the use of the rifaximin 200 mg tabletshas to be considered sub optimal due to the need up to six tablets a dayfor three months, resulting in a poor patient compliance. The 200 mgtablets of rifaximin have also been used in the treatment of Crohn'sdisease with dosages of 600 mg/day for 16 weeks as described by Shafran,I., Am. J. Gastroenterol., 2003, 98 (Suppl.) S-250.

Thus, there is a need in-the-art for a rifaximin pharmaceuticalformulation for the treatment of infections specifically located in theintestinal tract. Previous formulations, after administration, arereleased and spread between the stomach and the intestine. Thus, whenthe rifaximin finally reaches the intestinal tract, the concentration istoo low resulting in the need for increasing dosages. To maximize thetherapeutic efficacy of rifaximin in the treatment of bowel diseases,new pharmaceutical formulations are provided herein and include, forexample, rifaximin microgranules coated with a gastroresistant filmwhich dissolves releasing the antibiotic only in the intestinal tract.This novel formulation maximizes contact between the active ingredientand the intestinal mucous due, in part, to the high superficial area ofthe microgranules. The novel formulations also allow for ease of highand low dose administration, for example, in paediatric use.

The novel gastroresistant rifaximin formulations takes advantage formthe pH difference between the gastric environment (e.g., values fromabout 1.5 to about 4.0, depending on the state of fast or in presence ofmeal) and the intestinal lumen (e.g., values from 5.0 to about 7.5,depending of the tracts considered).

The novel forms also utilize the polymorphic forms of rifaximin.

The coating of pharmaceutical microgranules with gastroresistant film isa technique known by many years in the pharmaceutical field. It isgenerally performed in two steps: granulation and coating. Nevertheless,many active substances, including rifaximin, are characterized by a veryfine particle size, for example, in case of rifaximin approximately 50%of the particles has a particle diameter between 10 μm and 40 μm. Insuch condition it is very difficult using conventional systems likefluid bed coating or pan technology. Very often agglomeration occurs orrandom blend of coated and uncoated particles is commonly obtained.

We have found, and this is an object of the invention, that it ispossible to obtain enteric-coated microgranules of rifaximin by applyingthe fluid bed technology, which surprisingly allows in one step and atthe same time to perform the wet-granulation of the powder and thecoating of the formed microgranules with a polymer resistant to thegastric environment, commonly called enteric coating. With this approachthe chief disadvantages of the wet-granulation and microgranule coating,which are in separate steps involved as well as the time and labournecessary to carry out the entire procedure, especially on the largescale, are minimised. This result comes from a combination between therifaximin properties and a proper balancing the quantity of rifaximin,of enteric polymer, of plasticiser, and process parameters.

The efficiency of this technology in providing a complete coating layeraround rifaximin is demonstrated by SEM microscopy as reported in FIGS.1 a (Scanning electron microscopy of rifaximin gastroresistantmicrogranules) and 1 b (Scanning electron microscopy of single granuleof rifaximin gastroresistant microgranules), where it is clearly showthat rifaximin is fully coated by the enteric polymer. The particlessizes are quite homogeneous without large clots or very fine powder. Ifpresent, one or both of these aspects would have negative impact in anyfurther medicinal preparation.

As confirmation of the completeness of the coating, the dissolutionprofile of the gastroresistant microgranules of rifaximin shows thatrifaximin is completely retained at low pH and released at pH higherthan 5.0, as reported in FIG. 2 (Dissolution profiles).

In order to maximize the release of the active ingredient near theintestinal mucous membrane it has been utilized high pH differencebetween the gastric environment, values from 1.5 to 4.0, depending onthe state of fast or in presence of meal and the intestinal lumen,values from 5.0 to 7.5 depending of the tracts considered. For thispurpose, enteric polymeric materials having the property to solubilizeat pH values between 5.0 and 7.5 have been used, to include: methacrylicacid copolymers with an acrylic or methacrylic ester like methacrylicacid ethylacrylate copolymer (1:1) and methacrylic acidmethylmethacrylate copolymer (1:2), polyvinyl acetate phthalate,hydroxypropyl cellulose acetate phthalate and cellulose acetatephthalate, products available on the market for example with thetrademarks KOLLICOAT®, EUDRAGIT®, AQUATERIC®, AQOAT®.

The application of these gastroresistant films to rifaximin powder orgranules is performed with conventional apparatus for fluid-bed coatingtechnology. The film coating, dissolved in organic solvents or suspendedin water, is applied by spraying on powders or granules maintained insuspension with air in fluid bed systems. The most used organic solventsare: methylene chloride, methyl alcohol, isopropyl alcohol, acetone,tri-ethyl acetate and ethyl alcohol. Alternatively, the polymericgastroresistant material can be applied suspended in water. Thistechnique is preferable because it doesn't need the use of solvents andso it avoids the toxicological and safety related problems.

Other excipients with anti-agglomerative properties, like talc;plasticizing properties, like acetilated glycerides, diethylphthalate,propylene glycol and polyethylene glycol; surfactants like polysorbateand polyoxyethylenate esthers, anti-foam as well as anti-sticking agentscan be added together with the polymeric material.

The successful application of the above mentioned technology to thecoating of rifaximin powder is remarkable because it is not in thestate-of-art of fluid-bed technology to spray the enteric polymerdirectly on the active ingredient without any preliminary treatment likegranulation or layering the active ingredient on inert particles.Indeed, several drawbacks could occur without any powder pre-treatmentsuch as large clamp formation, large range of particle diameter,inhomogeneous composition of microgranules, no uniform coating layer.The occurrence of some of these drawbacks is common with rifaximin, thepowder of which is composed by a fine particles, and is extremelyhydrophobic, electrostatic, hygroscopic and difficult to be mixed withcommon excipients in powder. Moreover it has a predisposition tosegregate not allowing homogenous mixture. In presence of suchunfavourable characteristics to get coated rifaximin would required theuse of more than one step and a large quantity of excipients, whichwould limit the pharmaceutical strengths of human dosage.

As further advantage of the present invention, the gastroresistantmicrogranules of rifaximin prepared on the basis of the describedtechnology of the present invention can directly be used to fillcapsules or can be mixed with excipients and sweetener enhancers givingthe possibility of an aqueous suspension administration.

In addiction and more remarkably the gastroresistant microgranules ofrifaximin can also be directly used for tablet preparation throughdirect compression technology by adding conventional vehicles orcarriers. As additional advantage, the tablets can be scored in order tomodulate the dose strength or to be crushed to facilitate the ingestionwithout losing the gastroresistant property of the microgranules.

All these opportunities confer significant value to the technologydescribed in the present invention to prepare gastroresistantmicrogranules of rifaximin, making it suitable for a wide modulation ofdosages and pharmaceutical forms.

In conclusion, the present invention shows, with respect to othermarketed rifaximin preparations, remarkable improvements that can besummarized on the possibility to manufacture in only one stepsgastroresistant microgranules of rifaximin, which remain insoluble inthe stomach (e.g., at a range of pH between about 1.5 and about 4.0) andsoluble in the intestine (e.g., at higher pH, for example between about5.5 and about 7.5), to administer high dose, targeting the maximumrelease of the active ingredient in the intestine and at the same timemaximizing its contact with the intestinal mucous membrane because ofthe high superficial area of the microgranules.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is an image of microgranules of rifaximin.

FIG. 1B is a closer image of a single microgranule.

FIG. 2 is a line graph which shows the dissolution profiles ofgastroresistant rifaximin

FIG. 3 is a scanning electron microscope image of rifaximingastroresistant microgranules that are compressed in tablets.

DESCRIPTION OF THE INVENTION

The object of the present invention consists of pharmaceuticalformulations containing microgranules of rifaximin coated with agastroresistant polymer which is insoluble at pH values ranging between1.5 and 4.0 and soluble at pH values ranging between 5.0 and 7.5, oftheir preparation and their use in intestinal inflammatory boweldiseases and in particular in Crohn's disease.

The microgranules may be from between about 1 micron to about 900microns in diameter, or more preferably from between about 10 microns toabout 500 microns in diameter.

The gastroresistance can be obtained using any material insoluble at pHvalues ranging between about 1 to about 4.9, from about 1.4 to about4.2, or from about 1.5 and about 4.0. Suitable polymers may also besoluble at pH values ranging from between about 5.0 to about 7.0, 5.0 toabout 7.5, or 5.0 and about 7.7 and above.

Polymeric materials utilized in the gastroresistant rifaximinformulations solubilize, as discussed above, at pH values consist withthe intestinal lumen, for example, from between about 4.9 and about 7.7,and can be used as gastroresistant, entero-soluble coatings for drugrelease in the intestine when desired. Examples of suitable polymericmaterials include, for example, acrylic polymers, methacrylic acidcopolymers with an acrylic or methacrylic ester (e.g., methacrylic acidethylacrylate copolymer (1:1) and methacrylic acid methylmethacrylatecopolymer (1:2), polyvinyl acetate phthalate, hydroxypropyl celluloseacetate phthalate and cellulose acetate phthalate), as well as celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate. Commercially available products include, for example,KOLLIKOAT®, EDRAGIT® (e.g., EUDRAGIT 40), AQUATERIC®, AQOAT®.

The enteric materials, which are soluble at higher pH values, arefrequently used for colon-specific delivery systems and are employablein the gastroresistant rifaximin formulations described herein. Theenteric polymers used can also be modified by mixing with other coatingproducts that are not pH sensitive. Examples of such coating productsinclude, for example, the neutral methacrylic acid esters with a smallportion of trimethylammonioethyl methacrylate chloride, sold currentlyunder the trade names EUDRAGIT® and EUDRAGIT® RL; a neutral esterdispersion without any functional groups, sold under the trade namesEUDRAGIT® NE30D and EUDRAGIT® NE30, EUDRAGIT® 40; polysaccharides, likeamylose, chitosan, chondroitin sulphate, dextran, guar gum, inulin andpectin; and other pH independent coating products.

The polymer is from between about 5% and about 75% of the weight of themicrogranule. In other embodiments, the polymer is from between about10% and about 60%, 20% and about 55%, about 30% to about 80%, or 25% andabout 50% of the weight of the microgranule. The weight percent of thepolymer to the weight of the microgranule can depend, in part, on thepolymer used, the temperature of the polymer, the formulation (e.g., bagpill, capsule, etc.), and the pH at which the polymer is soluble.

The gastroresistant rifaximin microgranules may further comprise one ormore of a diluents, plasticizer, anti-agglomerative, anti-sticking,glidants, anti-foam surfactants, or colouring substances. These, alongwith other polymers and coating (e.g., protective coatings,over-coatings, and films) are described below.

Suitable ingredients can be incorporated into the coating formula suchas plasticizers, which include, for example, adipates, azelates,benzoates, citrates, isoebucates, phthalates, sebacates, stearates andglycols. Representative plasticizers include acetylated monoglycerides,butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate,dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, ethyleneglycol, propylene glycol, triacetin citrate, triacetin, tripropinoin,diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols,castor oil, triethyl citrate, polyhydric alcohols, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxydised tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-1-octylphthalate, di-1-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,glyceryl monocaprylate, and glyceryl monocaprate. Other various layers,as recognized by one of skill in the art are also envisioned. The amountof plasticizer used in the polymeric material typically ranges fromabout 10% to about 50%, for example, about 10, 20, 30, 40, or 50%, basedon the weight of the dry polymer.

Optional modifying components of a protective layer which can be usedover the enteric or other coatings include a water penetration barrierlayer (semi-permeable polymer) which can be successively coated afterthe enteric or other coating to reduce the water penetration ratethrough the enteric coating layer and thus increase the lag time of thedrug release. Coatings commonly known to one skilled in the art can beused for this purpose by coating techniques such as fluid bed coatingusing solutions of polymers in water or suitable organic solvents or byusing aqueous polymer dispersions. For example, useful materials includecellulose acetate, cellulose acetate butyrate, cellulose acetatepropionate, ethyl cellulose, fatty acids and their esters, waxes, zein,and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D,EUDRAGIT® NE 30D, EUDRAGIT® 40, AQUACOAT®, SURELEASE®, cellulose acetatelatex. Combinations of the polymers and hydrophilic polymers such ashydroxyethyl cellulose, hydroxypropyl cellulose (KLUCEL®, HerculesCorp.), hydroxypropyl methylcellulose (METHOCEL®, Dow Chemical Corp.),polyvinylpyrrolidone may also be used.

Anti-foaming agents can also be included in the gastroresistantrifaximin formulations. In one embodiment, the anti-foaming agent issimethicone. The amount of anti-foaming agent used typically comprisesfrom 0% to 0.5% of the final formulation. Other agents can be added toimprove the processability of a sealant or barrier layer. Such agentsinclude, for example, talc, colloidal silica, polyvinyl alcohol,titanium dioxide, micronized silica, fumed silica, glycerolmonostearate, magnesium trisilicate, and magnesium stearate, or amixture thereof.

The amount of polymer to be used in the gastroresistant formulations istypically adjusted to achieve the desired drug delivery properties,including the amount of drug to be delivered, the rate and location ofdrug delivery, the time delay of drug release, and the size of themultiparticulates in the formulation. The combination of all solidcomponents of the polymeric material, including co-polymers, fillers,plasticizers, and optional excipients and processing aids, typicallyprovides about 1% to about 50% weight of the core.

The gastroresistant rifaximin microgranules comprise rifaximin in apolymorphous form and/or a raw form. The forms in any microgranule maybe a mixture or may be a pure form. The form of rifaximin may depend, inpart, on the form of the rifaximin that is coated, on the composition ofexcipients, and on the process used to form the microgranules. Therifaximin polymorphous forms are selected from Form α, Form β, Form γ,Form δ, or Form ε of rifaximin, mentioned above.

The mixture containing the gastroresistant material is prepared bysuspending the components in demineralised water and homogenizing thesuspension with an high speed mixing system, preferably an Ultra Turaxhomogeniser, in order to obtain a homogeneous suspension containingbetween 15% and 30% of solid particles. The homogeneous suspensioncontaining the gastroresistant material can be applied by means of acoating system or a fluid bed apparatus.

In the current invention, fluid bed technology has been used. Themixture containing the active ingredient is maintained in suspension bya flux of warm air, at the same time the gastroresistant suspension issprayed by means of a jet applied in a top part (top spray) or in a lowpart (bottom spray—Wurster system) of the apparatus. For example, afluid bed apparatus type Glatt GPG 30 has been used with a Wurstersystem of 18 inch with a 1.8 mm spray jet.

Process parameters including the air entering temperature, the producttemperature and the speed of film application are specificallycontrolled. The speed of film application and the air temperature arebalanced to avoid overheating of the product resulting in anon-homogeneous gastroresistant microgranule formation (too fast dryingof the product) or, an agglomeration of the mixture to be coated to slowdrying of the product.

In formulating, for example, a 25 kg batch of gastroresistant rifaximin,a jet spray between 150 and 300 g/min may be used. A jet spray 150 and250 g/min, and pressures between 1.0 and 1.5 bar may also be used. Thespeed and pressure may be independently manipulated. The producttemperature, during the spraying is maintained at a constant temperaturebetween about 20° C. and about 40° C. The air temperature in entrancemay also be regulated at between about 40° C. and about 75° C.,preferably between about 60° C. and about 70° C.

The obtained gastroresistant microgranules are formulated for medicalpreparations in order to obtain, after adding water, a suspension withpleasant taste for the patients. Sweeteners agents like: sucrose,sorbitol, mannitol, saccharine, acesulfame, neohesperedine; suspendingagents like polyvinyl pyrrolidone (PVP), sodium carboxymethyl cellulose,pectin, xantan gum, agar and glidants like silica gel can be added tothe gastroresistant microgranules to this end.

The gastroresistant microgranules are mixed with the above mentionedexcipients in a suitable apparatus like a biconical mixer or V mixer forthe time necessary to obtain the homogeneity of the gastroresistantmicrogranules inside the mixture. The ratio between gastroresistantmicrogranules and excipients is between 1:0.1 and 1:10, preferablybetween 1:0.5 and 1:5. The obtained mixture can be divided in bagscontaining a quantity of rifaximin between 1 mg and 3000 mg, preferablybetween 50 mg and 800 mg.

The obtained gastroresistant microgranules of rifaximin can be directlycompressed in tablet after having mixed with appropriate excipients suchas diluents such as dicalcium phosphate, calcium sulphate, cellulose,microcrystalline cellulose (AVICEL®), hydroxypropyl methyl cellulose,corn starch, lactose, kaolin, mannitol, sodium chloride, dry starch;binders such as starch, gelatine, sugars as sucrose, glucose, dextrose,lactose, synthetic gum, sodium alginate, carboxymethyl cellulose,methylcellulose, polyvinylpyrrolidone, polyethylene glycol,ethylcellulose, water, waxes, alcohol; lubricants such as talc,magnesium stearate, calcium stearate, stearic acid, hydrogenatedvegetable, oils, polyethylenglycole; glidants such as colloidal silicondioxide, talc; disintegrants such as corn and potato starch,croscarmelose, crospovidone, sodium starch glycolate, colouring agents,sweeteners such as sucrose, sorbitol, mannitol, saccharine, acesulfame,neohesperedine.

Conventional technology and apparatus known to expert-of-art of tabletpreparation can be applied. The gastroresistant microgranules are mixedwith the above mentioned excipients in a suitable apparatus like abiconical mixer or V mixer for the time necessary to obtain thehomogeneity of the gastroresistant microgranules inside the mixture.

The gastroresistant granules of rifaximin have good properties inrespect of ability to flow freely, cohesiveness and lubrication,therefore the ratio between gastroresistant microgranules and excipientsis between 1:0.2 and 1:0.05, preferably between 1:0.15 and 1:0.1. Theobtained mixture can be pressed in order to obtain, using a suitablepunch, tablets containing a quantity of rifaximin between 50 mg and 600mg, preferably between 100 mg and 500 mg. As described above thefavourable properties of Rifaximin gastroresistant microgranules allowachieving a suitable blend for direct compression with the addiction ofminimal quantity of excipients. The possibility to obtain tablets usinga blend containing up to 93% of gastroresistant microgranules presents afurther advantage: it allows to maintain the dose of 400 mg in asuitable size to maintain a good compliance for the patient.

Tablets can be successively coated with a conventional hydrophilic filmto achieve taste-masking properties and improve appearance. Suitablematerials could be: hydroxyethyl cellulose, hydroxypropyl cellulose(KLUCEL®, Hercules Corp.), hydroxypropyl methylcellulose (METHOCEL®, DowChemical Corp.), polyvinylpyrrolidone.

The tablet containing rifaximin gastroresistant microgranules can befilm-coated following conventional procedure known to someone skilled inthe art selecting as polymer one or more of cellulose and itssubstitutes such as hydropropylcellulose hydromethylcellulose,hydropropyl-methylcellulose. Alternatives to the cellulose ethers arecertain acrylics, such as metacrylate and methylmetacrylate copolymers.Polymers can be employed as solutions either aqueous or organicsolvent-based system. Incorporating a plasticiser the flexibility of thecoating film is improved; by addition of plasticisers it is reduced therisk of film cracking and it is improved the adhesion of the film to thesubstrate. Examples of typical plasticisers include glycerin, propyleneglicol, polyethylene glycols, triacetin, acetylated monoglycerides,citrate esthers and phtalate esthers. Colorants usually are used toimprove the appearance of the product. Water-soluble and/or organicsolvent-soluble dyes can be used like albumin lake, titanium dioxide,iron oxide. Finally, stabilisers such as EDTA can be added to thecoating.

The picture shown in FIG. 3 (Scanning electron microscopy of rifaximingastroresistant microgranules compressed in the tablets) and the data ofFIG. 2 show that the compression does not alter the integrity of thegastroresistant layer of the microgranules compressed in the tablets.

Furthermore, the obtained gastroresistant microgranules of rifaximinhave such favourable properties regarding the particle size and thecapacity of flow freely to be directly used, with the addiction of inertdiluents and glidants to fill in hard gelatine capsules. Examples oftypical diluents include dicalcium phosphate, calcium sulphate,cellulose, microcristallyne cellulose, hydroxypropylmethylcellulose,corn starch, lactose, caolin, mannitol, sodium chloride, dry starch,from between about 1 and to about 225 mg. In this case the density ofgastroresistant microgranules, between 0.25 and 0.45 mg/ml allows tofill about 140-250 mg of Rifaximin in conventional 000 hard gelatinecapsules according to the content of Rifaximin in the gastroresistantmicrogranules.

All the medicine preparation, namely thermo welded bags, tablets andcapsules can be usefully used in the therapy of inflammatory boweldisease to include Crohn's disease.

The following examples have to be considered as a further illustrationof the object of the invention and not as a limitation.

Example 1 Rifaximin Preparation in Gastroresistant Microgranules

In a fluid bed apparatus, Glatt GPC 30, with a Wurster system of 18inches with a 1.8 mm spray jet, 25000 g of rifaximin powder and 125 g ofAerosil as fluidiser are loaded. Contemporaneously in a mixer underagitation a suspension is prepared using 48107 g of demineralised water,9281 g of methacrylic acid ethylacrylate copolymer marketed under thetrademark KOLLICOAT® MAE 100 P, 1392 g propylglycol, 2475 g of talc, 557g of titanium dioxide FU and 62 g of iron oxide E 172. The solidcomponents of the suspension are homogeneously mixed in demineralisedwater with an high speed homogeniser (Ultra Turrax). The preparedsuspension feeds the spray system of the fluid bed apparatus andnebulized, at a pressure between 1.0 and 1.5 bar, trough the 1.8 mmnozzle on the mixture of rifaximin powder and Aerosil 200 maintained insuspension in the fluid bed by a warm air flow.

The applied conditions are described in table 1:

TABLE 1 Pre-warm Application of Process parameters phase coatingsolution Drying Air flow in entrance 400 ± 100 550 ± 100 350 ± 50(m³/hour) Air temperature in entrance 60 ± 2  60° C. ± 10 50 ± 2 (° C.)Product temperature (° C.) 32 25-27 30 ± 2 Jet pressure (bar) 1-1.5 ±0.1 (initial phase) Jet speed (g/min) 150-200

The obtained microgranules are submitted to granulometry analysis byLight Scattering technology using Malvern Mastersizer 2000 apparatusobtaining the following results:

-   -   100%<200 micron    -   99.17%<150 micron    -   90.03%<100 micron    -   48.37%<50 micron    -   6.20%<10 micron

The rifaximin in the gastroresistant microgranule preparationcorresponds to 61.4% of the total particle weight.

Example 2 SEM Microscopy of Gastroresistant Microgranules of Rifaximin

A SEM Philips 515 instrument is used for the observations.

Rifaximin gastroresistant microgranules are sputtered with gold bycurrent stream of 30 mA, getting an Au-layer of about 100 nm. Anaccelerating voltage of 15 kV is applied.

The images are digitally recorded with a CCD camera.

An image of microgranules of rifaximin is shown in FIG. 1A, while inFIG. 1B a detail of a single microgranule is shown.

Example 3 Gastroresistant Microgranules of Rifaximin Prepared in ThermoWelded Bags

9.12 Kg of gastroresistant rifaximin microgranules prepared according tothe example 1, 19.58 Kg of sorbitol, 0.49 Kg of aspartame, 0.21 Kg ofanhydrous citric acid, 2.10 Kg of pectin, 2.10 Kg of mannitol, 0.21 Kgof neohesperidine DC, 1.12 Kg of cherry flavour and 0.07 Kg of silicagel are sieved on a sieve with mesh of 0.5 mm and then mixed for 20minutes in a V mixer. The resulting mixture is divided in thermo weldedbags containing 5 grams of product corresponding to 800 mg of rifaximin.In the following Table 2 the composition of the medicinal speciality,thermo welded bag, is reported:

TABLE 2 Amount Components (mg) % Gastroresistant rifaximin microgranules1303 26.06 (corresponding to 800 mg of rifaximin) Aspartame 70 1.40Anhydrous citric acid 30 0.60 Pectin 300 6.00 Mannitol 300 6.00Neohesperidin DC 30 0.60 Sorbitol 2797 55.94 Cherry-flavour 160 3.20Silica gel 10 0.20

Example 4 Gastroresistant Microgranules of Rifaximin Prepared inCompressed Tablets

9.3 Kg of gastroresistant rifaximin microgranules prepared according tothe example 1, 593 g of Sodium Starch Glycolate, 100 g of magnesiumstearate are sieved on a sieve with mesh of 0.5 mm and then mixed for 20minutes in a V mixer. The resulting mixture is compressed using a rotarytabletting machine (Fette 1200) equipped with oblong, scored 19×9 mmpunches at the final weight of 718 mg (corresponding to a content of 400mg of rifaximin).

The tablet composition is reported in Table 3.

TABLE 3 Amount Tablet composition mg % Rifaximin gastroresistant 650.0090.53 microgranules (corresponding to 400 mg of rifaximin) sodium 34.954.87 carboxymethylcellulose Avicel PH 101 24.31 3.34 Mg-stearate 8.741.21 718.00 100.00

The tablets are then coated, using conventional pan equipment, with ahydroxypropylmethylcellulose film in order to improve appearance andachieve taste mask properties. The unitary film composition is reportedin Table 4:

TABLE 4 Amount Coating composition (mg) HPMC 14.07 Titanium dioxide 4.10Na-EDTA 0.05 Propylene glycol 1.37 Red Iron Oxide E 172 0.41

Example 5 Gastroresistant Microgranules of Rifaximin Prepared in HardCapsule

9.0 Kg of gastroresistant rifaximin microgranules prepared according tothe example 1, are blended and sieved on 0.5 mm with 110 g of talc and1.1 kg of lactose. The resulting mixture is introduced in hard gelatinecapsules type 000 using a conventional equipment like Zanasi LZ64 at afinal weight of 461.00, corresponding to a content of about 270 mg ofrifaximin. The capsule composition is reported in Table 5.

TABLE 5 Amount Capsule composition mg % Rifaximin gastroresistant 406.0088.01 granules (corresponding to 270 mg of rifaximin) Talc 5.00 1.01Lactose 50.00 10.8

Example 6 Dissolution Performance of Gastroresistant Microgranule ofRifaximin Medicinal Preparations

The gastroresistance of the pharmaceutical preparation is evaluatedaccording to what described at page 247 of the US Pharmacopeia (USP),28a Ed.

The dissolution test of medicinal preparations containinggastroresistant microgranules of rifaximin, described in examples 1, 3and 4 and consisting of rifaximin gastroresistant microgranules, thermowelded bags containing rifaximin gastroresistant microgranules, andtablets containing rifaximin gastroresistant microgranules,respectively, are evaluated by using the following conditions:

Equipment: SOTAX AT7 Smart

Medium: HCl 0.1 N, pH 1; after 2 hours a phosphate buffer with 2% ofSodium Lauryl Sulphate is added to bring up the pH to 6.8

Stirring speed: 100 rpm

Temperature: 37° C.

Sampling time: 120, 135, 150, and 180 min.

The content of dissolved rifaximin is measured by a HPLC method.

The results, reported in Table 6, are the average of six measures andare expressed as percent of dissolution over the total amount ofrifaximin.

TABLE 6 Dissolution (%) Medium & pH Time (min) Microgranules TabletsBags HCl 0.1 N, pH 1 120 2.41 1.07 2.57 Phosphate buffer, pH 6.8 13593.8 67.9 90.3 Phosphate buffer, pH 6.8 150 95.4 81.6 95.1 Phosphatebuffer, pH 6.8 165 97.2 88.1 96.4 Phosphate buffer, pH 6.8 180 97.4 93.196.2

After 12 months of storage at 25° C. microgranules, prepared as inExample 1, show a similar dissolution profile, precisely a dissolutionof 2.2% after 120 min at pH 1 in 0.1 N hydrochloric acid and of 91.1%after 60 min in phosphate buffer at pH 6.8.

Example 7 Treatment of Crohn's disease

The medicinal rifaximin preparation containing gastroresistantmicrogranules described in example 3 has been used in a clinicalmulti-center randomised trial versus placebo in patients affected byCrohn's disease. 55 Crohn's disease patients in acute, mild to moderategrade, phase, having CDAI (Crohn Disease Active Index) value between 200and 300, have been recruited. The primary end point was represented bythe percentage of the patients in clinic remission defined as CDAI lowerthan 150 points at the end of the study. The patients, randomised in twogroups: group A, of 27 patients and group B of 28 patients, have beentreated for 12 weeks according to the following therapeutic schemes:

Group A: rifaximin 800 mg, administrated 2 times a day for a totaldosage equal to 1600 mg/die;

Group B: placebo, administrated 2 times in a day in a such quantity tocorrespond to the content of the dose of the active principle.

The primary end point, the clinical remission after 12 weeks of therapy,is achieved by 51.9% of the patients with the gastroresistantformulation and by 32.1% of the patient treated with placebo. Moreoveronly one patients of the group treated with rifaximin has been forcedearly to leave the clinical trial because of the therapeutic failure,while nine patients treated with placebo discontinued the treatment.

The results are summarised in Table 7

TABLE 7 Number Number of of clinical therapeutic Group remission failureA (rifaximin) 27 patients 14 (51.9%) 1 (3.4%)  B (placebo) 28 patients 9 (32.1%) 9 (32.1%)

Example 8 Treatment of Crohn's Patients Characterized by a Protein CReactive Value Higher than Normal

At the beginning of the treatment, 31 patients had a protein C reactivevalue, an index of inflammation in course, higher than normal. Thepatients have been divided into two groups: one of 16 treated withrifaximin and the other treated with placebo, as described in example 3.

The primary end point, the clinical remission, has been obtained in62.5% of the patients treated with the new formulation of rifaximin andin 20.5% only of the patients treated with placebo. Moreover, none ofthe patients of the subgroup treated with rifaximin dropped from thestudy for therapeutic failure, unlike 6 of the patients of the subgrouptreated with placebo.

The Table 8 shows the obtained results.

TABLE 8 Subgroup with protein C value Number of clinical Number ofhigher than normal values remission therapeutic failure 16 patientstreated 10 (62.5%) 0 (0%)  with rifaximin 15 patients treated withplacebo 3 (20%)  6 (40%)

The incidence of side effects has been similar in the two groupsconfirming the excellent tolerability of the rifaximin formulation incontinuous and prolonged use.

The invention claimed is:
 1. A gastroresistant rifaximin microgranulecomprising rifaximin directly coated with a gastroresistant polymericmaterial formulation, wherein said gastroresistant polymeric materialformulation comprises a gastroresistant polymer which is insoluble at pHvalues from about 1.5 to about 4 and is soluble at pH values from about5.0 to about 7.5, wherein the gastroresistant rifaximin microgranule hasa diameter of from about 1 micron to about 900 microns, wherein saidrifaximin is released at a pH higher than 5.0, and wherein thegastroresistant polymer is selected from the group consisting of acrylicpolymer, methacrylic acid copolymers, methacrylic acid copolymers withan acrylic or methacrylic ester, cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, polyvinyl acetate phthalate, methacrylic acid ethylacrylatecopolymer, and mixtures thereof.
 2. The gastroresistant rifaximinmicrogranule according to claim 1, wherein said diameter of thegastroresistant rifaximin microgranule is from about 10 microns to about500 microns.
 3. The gastroresistant rifaximin microgranule according toclaim 1, wherein said rifaximin is in a polymorphous form or a raw formor a combination thereof.
 4. The gastroresistant rifaximin microgranuleaccording to claim 3, wherein the polymorphous form of rifaximin isselected from the group consisting of Form α, Form β, Form γ, Form δ,Form ε and combinations thereof.
 5. The gastroresistant rifaximinmicrogranule according to claim 4, wherein the polymorphous form is formβ.
 6. The gastroresistant rifaximin microgranule according to claim 1,further comprising a fluidizer.
 7. The gastroresistant rifaximinmicrogranule according to claim 1, wherein the polymer is selected fromthe group consisting of cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,polyvinyl acetate phthalate, co-polymers of methacrylic acid andcombinations thereof.
 8. The gastroresistant rifaximin microgranuleaccording to claim 1, wherein the the gastroresistant polymer isselected from the group consisting of methacrylic acid ethylacrylatecopolymer (1:1), methacrylic acid methylmethacrylate copolymer (1:2) andcombinations thereof.
 9. The gastroresistant rifaximin microgranuleaccording to claim 1, wherein the amount of polymer is from about 5% toabout 75% by weight with respect to the total weight of themicrogranule.
 10. The gastroresistant rifaximin microgranule accordingto claim 1, wherein the gastroresistant polymeric material formulationfurther comprises an excipient selected from the group consisting ofdiluents, plasticizers, anti-agglomerative excipients, glidants,surfactants, anti-foaming excipients, coloring substances anti-stickingagents and combinations thereof.
 11. The gastroresistant rifaximinmicrogranule according to claim 10, wherein said plasticizer is selectedfrom the group consisting of adipates, azelates, benzoates, citrates,isoebucates, phthalates, sebacates, stearates, glycols and combinationsthereof.
 12. The gastroresistant rifaximin microgranule according toclaim 10, wherein said plasticizer is selected from the group consistingof acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyltartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethylglycolate, glycerin, ethylene glycol, propylene glycol, triacetincitrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetylmonoglyceride, polyethylene glycols, castor oil, triethyl citrate,polyhydric alcohols, acetate esters, gylcerol tri acetate, acetyltriethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate,epoxidized tallate, triisooctyl trimellitate, diethylhexyl phthalate,di-n-octyl phthalate, di-1-octyl phthalate, di-1-decyl phthalate,di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyltrimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate,di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate,glyceryl monocaprate and combinations thereof.
 13. The gastroresistantrifaximin microgranule according to claim 10, wherein said plasticizeris selected from the group consisting of ethylene glycol, propyleneglycol, glycerin, polyethylene glycols and combinations thereof.
 14. Thegastroresistant rifaximin microgranule according to claim 13, whereinsaid plasticizer is present in an amount from about 10% to about 50%based on the weight of the dry polymer.
 15. A pharmaceutical formulationcomprising the gastroresistant rifaximin microgranule according to claim1, wherein said gastroresistant rifaximin microgranules are present inthe pharmaceutical formulation in a therapeutically effective amount totreat inflammatory bowel diseases.
 16. The pharmaceutical formulationaccording to claim 15, wherein said gastroresistant rifaximinmicrogranules are present in the form of thermo welded bags, tablets orhard-gelatin capsules.
 17. The pharmaceutical formulation according toclaim 16, in the form of a thereto welded bag comprising from about 1 toabout 3000 mg of said gastroresistant rifaximin microgranules, from 0 toabout 450 mg of a sweetening agent, from 0 to about 50 mg of organicacid from about 1 to about 500 mg of a suspending agent from between 0to about 500 mg of mannitol, from 0 to about 4000 mg of sugar alcohol;from 0 to about 300 mg of a flavoring agent; and from 0 to about 100 mgof a glidant.
 18. The pharmaceutical formulation according to claim 17,wherein the sweetening agent is selected from one or more of sorbitol,aspartame, sugar, xylitol, lactitol, sodium cyclamate, dextrose,fructose, glucose, lactose, sucrose, or neohesperidin DC; wherein theorganic acid is selected from one or more of citric acid, acetic acid,adipic acid, fumaric acid, glutaric acid, malic acid, succinic acid, ortartaric acid; wherein the suspending agent is selected from one or moreof polyvinyl pyrrolidone (PVP), sodium carboxymethyl cellulose, pectin,xanthan gum, or agar agar; wherein the sugar alcohol is selected fromone or more of lactitol, maltitol, mannitol, sorbitol, xylitol, xanthangum, dextrins, or maltodextrins; wherein the flavoring agent is selectedfrom one of more of a fruit flavor or a vegetable flavor; and whereinthe glidant is selected from one or more of silica gel, magnesiumstearate, or talc.
 19. The pharmaceutical formulation according to claim16, in the form of a tablet comprising from about 50 to about 1000 mg ofsaid gastroresistant rifaximin microgranules; from about 1 to about 500mg of a diluent agent; from 0 to about 500 mg of a binder agent; from 0to about 20 mg of a lubricant agent; from about 0 to about 20 mg of aglidant agent; from 0 to about 200 mg of a disintegrant agent;optionally a coloring agent and optionally a sweetener agent.
 20. Thepharmaceutical formulation according to claim 19, wherein the diluentagent is selected from one or more of dicalcium phosphate, calciumsulphate, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, corn starch, lactose, kaolin, mannitol sodium chloride, anddry starch; wherein the binder agent is selected from one or more ofstarch, gelatine, sugars as sucrose, glucose, dextrose, lactose,synthetic gum, sodium alginate, carboxymethyl cellulose,methylcellulose, polyvinylpyrrolidone, polyethylene glycol,ethylcellulose, water, waxes, and alcohol; wherein the lubricant agentis selected from one or more of tale, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils, and polyethyleneglycol; Wherein the glidant agent is selected from one or more ofcolloidal silicon dioxide, and talc; wherein the disintegrant agent isselected from one or more of sodium carboxymethylcellulose, corn orpotato starch, croscarmelose, crospovidone, and sodium starch glycolate;wherein the coloring agent is selected from one or more of titaniumdioxide, and iron oxide; and wherein the sweetener agent is selectedfrom one or more of sucrose, sorbitol, mannitol, saccharine, acesulfame,and neohesperedine.
 21. The pharmaceutical formulation according toclaim 19, wherein said tablets are film-coated, wherein said filmcomprises from 0 to about 50 mg of a polymer selected from one or moreof cellulose, hydropropylcellulose, hydromethylcellulose,hydropropylmethylcellulose, acrylics, methacrylate, or methylmetacrylatecopolymers from 0 to about 5 mg of a plasticizer agent selected from oneor more of glycerin, propylene glycol, polyethylene glycols, triacetin,acetylated monoglycerides, citrate esters or phthalate esters; from 0 toabout 1 mg of a stabilizing agent; and from between 0 to about 10 mg ofa coloring agent selected from one or more of albumin lake, titaniumdioxide, or iron oxide.
 22. The pharmaceutical formulation according toclaim 21, wherein the stabilizing agent is EDTA.
 23. The pharmaceuticalformulation according to claim 16, in the form of hard-gelatin capsulescomprising from about 50 to about 450 mg of said gastroresistantrifaximin microgranules; from 0 to about 25 mg of a lubricant agent; andfrom about 1 to about 225 mg of a diluent agent.
 24. The pharmaceuticalformulation according to claim 23, wherein the lubricant agent isselected from one or more of talc, magnesium stearate, calcium stearate,stearic acid, hydrogenated vegetable oils, and polyethylene glycol; andthe diluent agent is selected from one or more of dicalcium phosphate,calcium sulfate, cellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, corn starch, lactose, kaolin, mannitol,sodium chloride and dry starch.
 25. The gastroresistant rifaximinmicrogranule according to claim 1, wherein 2.4 percent of the totalamount of rifaximin dissolves from said microgranule after 120 min in0.1 N HCl at pH 1 at 37° C. while stirring at 100 rpm.
 26. A method ofadministering rifaximin to a subject, the method comprising: identifyinga subject in need thereof, obtaining a pharmaceutical formulationcomprising gastroresistant rifaximin microgranules according to claim 1,and orally administering the formulation to the subject.
 27. The methodof claim 26, wherein at least a portion of the rifaximin is released inthe small intestine, colon, and rectum.
 28. The method of claim 26,wherein the subject suffers from a condition selected from the groupconsisting of colitis, Crohn's disease, and irritable bowel syndrome.29. The method of claim 28, wherein the value of C-reactive protein ofthe patients suffering from Crohn's diseases is higher than thestandard.
 30. A method of preparing a pharmaceutical formulationcomparing gastroresistant rifaximin microgranules according to claim 1,comprising: spraying through a nozzle an aqueous suspension containingrifaximin, at least one gastroresistant polymer and at least onepharmaceutical excipient into a fluid bed apparatus wherein the sprayingis under a pressure between 1.0 and 1.5 bar and at a flow speed between150 and 300 g/min and wherein rifaximin is maintained in suspension inthe aqueous suspension by a flux of warm air.